Prenatal vitamin C and E supplementation in smokers is associated with reduced placental abruption and preterm birth: a secondary analysis.

OBJECTIVE: Smoking and pre-eclampsia (PE) are associated with increases in preterm birth, placental abruption and low birthweight. We evaluated the relationship between prenatal vitamin C and E (C/E) supplementation and perinatal outcomes by maternal self-reported smoking status focusing on outcomes known to be impacted by maternal smoking. DESIGN/SETTING/POPULATION: A secondary analysis of a multi-centre trial of vitamin C/E supplementation starting at 9-16 weeks in low-risk nulliparous women with singleton gestations. METHODS: We examined the effect of vitamin C/E by smoking status at randomisation using the Breslow-Day test for interaction. MAIN OUTCOME MEASURES: The trial's primary outcomes were PE and a composite outcome of pregnancy-associated hypertension (PAH) with serious adverse outcomes. Perinatal outcomes included preterm birth and abruption. RESULTS: There were no differences in baseline characteristics within subgroups (smokers versus nonsmokers) by vitamin supplementation status. The effect of prenatal vitamin C/E on the risk of PE (P = 0.66) or PAH composite outcome (P = 0.86) did not differ by smoking status. Vitamin C/E was protective for placental abruption in smokers (relative risk [RR] 0.09; 95% CI 0.00-0.87], but not in nonsmokers (RR 0.92; 95% CI 0.52-1.62) (P = 0.01), and for preterm birth in smokers (RR 0.76; 95% CI 0.58-0.99) but not in nonsmokers (RR 1.03; 95% CI 0.90-1.17) (P = 0.046). CONCLUSION: In this cohort of women, smoking was not associated with a reduction in PE or the composite outcome of PAH. Vitamin C/E supplementation appears to be associated with a reduction in placental abruption and preterm birth among smokers.

Decidual GM-CSF is a critical common intermediate necessary for thrombin and TNF induced in-vitro fetal membrane weakening.

INTRODUCTION: Inflammation/infection and decidual bleeding/abruption are highly associated with pPROM. As no animal model for pPROM exists, we have developed an in-vitro model system for the study of human fetal membrane (FM) weakening/rupture. Using it we have demonstrated that both TNF/IL-1 (modeling inflammation) and thrombin (modeling bleeding) weaken full thickness FM in a dose dependent manner concomitant with inducing biochemical changes similar to those seen in the FM physiological weak zone. METHODS: As the physiological site of infection and bleeding is the choriodecidua (CD), we modified our model system with full thickness FM tissue mounted on modified Transwell culture inserts to permit directional TNF/thrombin exposure on the decidua only (rather than both sides of the FM). After incubation, medium was sampled separately from the CD facing (maternal side) or from the amnion facing (fetal side) compartments and probed for cytokine release and confirmed with western blots. The FM was strength tested within the insert. RESULTS: Full-thickness FM fragments exposed to TNF or thrombin on CD side only showed dose dependent weakening and biochemical changes consistent with previous reports. Concomitantly, GM-CSF increased markedly on the CD but not the amnion side. Numerous proteases including MMP1 and MMP3 also increased on the CD side. Pre-incubation with GM-CSF antibody blocked both thrombin and TNF induced weakening. Finally, GM-CSF weakened FM in a dose dependent manner. DISCUSSION: GM-CSF is a critical common intermediate in the thrombin and TNF FM weakening pathways.

Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population?

OBJECTIVE: To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women. DESIGN: A nested case-control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by pre-eclampsia and 468 normotensive nonproteinuric controls. SETTING: A multicentre study in 16 academic medical centres in the USA. POPULATION: Low-risk nulliparous women. METHODS: Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9-12, 15-18 and 23-26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics. MAIN OUTCOME MEASURES: Change in PlGF, sFlt-1 and sEng. RESULTS: Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not pre-eclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64-99), 77% (95% CI 50-93) and 77% (95% CI 50-93) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester. CONCLUSION: Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia.

Vitamin D status and recurrent preterm birth: a nested case-control study in high-risk women.

OBJECTIVE: To determine whether vitamin D status is associated with recurrent preterm birth, and any interactions between vitamin D levels and fish consumption. DESIGN: A nested case-control study, using data from a randomised trial of omega-3 fatty acid supplementation to prevent recurrent preterm birth. SETTING: Fourteen academic health centres in the USA. POPULATION: Women with prior spontaneous preterm birth. METHODS: In 131 cases (preterm delivery at <35 weeks of gestation) and 134 term controls, we measured serum 25-hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography-tandem mass spectrometry (LC-MS) from samples collected at baseline (16-22 weeks of gestation). Logistic regression models controlled for study centre, maternal age, race/ethnicity, number of prior preterm deliveries, smoking status, body mass index, and treatment. MAIN OUTCOME MEASURES: Recurrent preterm birth at <37 and <32 weeks of gestation. RESULTS: The median mid-gestation serum 25(OH)D concentration was 67 nmol/l, and 27% had concentrations of <50 nmol/l. Serum 25(OH)D concentration was not significantly associated with preterm birth (OR 1.33; 95% CI 0.48-3.70 for lowest versus highest quartiles). Likewise, comparing women with 25(OH)D concentrations of 50 nmol/l, or higher, with those with <50 nmol/l generated an odds ratio of 0.80 (95% CI 0.38-1.69). Contrary to our expectation, a negative correlation was observed between fish consumption and serum 25(OH)D concentration (-0.18, P < 0.01). CONCLUSIONS: In a cohort of women with a prior preterm birth, vitamin D status at mid-pregnancy was not associated with recurrent preterm birth.

The effects of thrombin and cytokines upon the biomechanics and remodeling of isolated amnion membrane, in vitro.

Abruption-induced thrombin generation and inflammation/infection induced cytokine production have both been associated with fetal membrane (FM) weakening and preterm premature rupture of the fetal membranes (PPROM). Using our in vitro model system we have demonstrated that thrombin, and separately the cytokines, tumor necrosis factor-alpha (TNFα) and interleukin-1-beta (IL-1ß), remodel and weaken full thickness FM. Additionally, we have reported that the anti-oxidant and NFκB inhibitor, alpha-lipoic acid (LA), blocks these thrombin and cytokine induced effects. The purpose of these studies was to determine whether thrombin and cytokines directly weaken the amnion membrane (AM), the major load-bearing component of FM. Isolated AM or full thickness FM fragments from unlabored Cesarean deliveries were incubated with thrombin, TNFα, or IL-1ß, for 48 h. Rupture strength (breaking force) of each fragment was thereafter determined using our published methodology. Biochemical evidence of remodeling and apoptosis; immunoreactive Matrix Metalloproteinase 9 (MMP9), Tissue Inhibitor of Matrix Metalloproteinase 3 (TIMP3) and cleaved poly (ADP-ribose) polymerase (C-PARP) levels in tissue extracts, were determined by western blot and densitometry. Thrombin induced a dose-dependent weakening of isolated AM (P < 0.001) coupled with dose dependent increases in PARP cleavage, and reciprocal increases and decreases, respectively, in MMP9 and TIMP3 protein (all P < 0.01). Thrombin receptor activating peptide-6 (TRAP) also weakened isolated AM. Neither TNFα nor IL-1ß weakened isolated AM. However, both cytokines weakened AM when it was incubated together with the choriodecidua as part of full thickness FM (P < 0.001). Cytokine-conditioned choriodecidua medium also weakened isolated AM (P < 0.001). Under conditions in which cytokines weakened the AM, the changes in MMP9, TIMP3 and PARP cleavage were consistent with those seen after thrombin incubation. LA blocked the FM weakening and remodeling effects. In summary, thrombin weakens AM directly whereas cytokines weaken AM indirectly by causing the release of soluble intermediates from the choriodecidua.

Alpha-lipoic acid inhibits thrombin-induced fetal membrane weakening in vitro.

Cytokine-mediated inflammation and abruption-induced thrombin generation are separately implicated in matrix metalloproteinase (MMP)-mediated weakening of fetal membranes (FM) leading to preterm premature rupture of the fetal membranes (PPROM). At term, FM of both labored vaginal and unlabored Cesarean deliveries exhibit a weak zone overlying the cervix exhibiting ECM remodeling characterized by increased MMP9 protein and activity. We have reproduced these biochemical changes as well as FM weakening in vitro using tumor necrosis factor-alpha (TNF) and interleukin (IL)-1ß, inflammatory cytokines implicated in PPROM. Additionally, we have reported that the antioxidant and NFκB inhibitor alpha-lipoic Acid (LA) blocks these TNF-induced effects. We now present the first direct evidence that thrombin also can induce FM weakening in vitro, and LA treatment inhibits this thrombin-induced-weakening. Full thickness FM fragments from unlabored Cesarean deliveries were incubated with increasing doses of thrombin (0-100 u/ml) for 48 h. Fragments were then strength tested (breaking force and work to rupture) using our published methodology. MMP3 and 9 levels in tissue extracts were determined by Western blot and densitometry. To determine the effect of LA, FM fragments were incubated with control medium or 10 u/ml thrombin, with or without 0.25 mM LA. Strength testing and MMP induction were determined. Thrombin induced a dose-dependent decrease in FM strength (42% baseline rupture force and 45% work to rupture) coupled with a dose-dependent increase in MMP3 and 9 expression (all p < 0.001). Treatment of FM with 0.25 mM LA completely inhibited thrombin-induced FM weakening and MMP expression (all p < 0.001). Thrombin treatment of cultured FM induces mechanical weakening and increased MMP3 and 9. Treatment of FM with LA inhibits these thrombin-induced effects. We speculate LA may prove clinically useful in prevention of PPROM associated with abruption.

Preterm prediction study: is socioeconomic status a risk factor for bacterial vaginosis in Black or in White women?

Bacterial vaginosis (BV), an important risk factor for preterm birth, is a more common infection in Black compared with White pregnant women. Because Black women in the United States are more likely to have lower measures of socioeconomic status (SES), this study examined the hypothesis that BV is associated with low SES. The project evaluated data from the Preterm Prediction Study of 2,929 women prospectively followed during their pregnancies. The women, who were screened for BV at 24 and 28 weeks of gestation, underwent a structured interview to evaluate demographic factors, SES, home and work environment, drug or alcohol use, and prior medical history. Black women in the study had many measures of lower SES compared with the White women, and reported less use of tobacco, alcohol and drugs. In neither the Black nor White women was an association found between BV and measures of SES (with the sole exception of "absence of a home telephone"). Most measures of SES do not explain the difference in rates of BV in Black and in White pregnant women.

Outcome after successful resuscitation of babies born with apgar scores of 0 at both 1 and 5 minutes.

OBJECTIVE: Our purpose was to evaluate the outcome of infants who underwent successful resuscitation after initial Apgar scores of 0 at both 1 and 5 minutes. STUDY DESIGN: Eligible infants were identified through the perinatal database at the University of Tennessee, Memphis. Hospital records and long-term outcomes, where available, of babies who met the above criteria occurring between January 1986 and February 1999 were reviewed. RESULTS: Thirty-three of 81,603 infants (0.4/1000 births) met our study criteria. Twenty-two (67%) babies died during hospitalization. Mortality decreased significantly from 100% for babies with a birth weight of <750 g to 38% for those weighing > or =2500 g at birth (P =.03). All 6 babies delivered before 26 weeks' gestation died. The incidence of 10-minute Apgar scores >0 was significantly higher among survivors than among those who subsequently died (82% vs 33%, P <.05). Nine survivors had hypoxic-ischemic encephalopathy diagnosed before discharge. Of the 7 infants with available follow-up, 4 had significant persisting morbidity. Two infants had normal neurologic examinations at follow-up. CONCLUSION: Survival in babies born with 1- and 5-minute Apgar scores of 0 is predicted by birth weight, gestational age, and 10-minute Apgar score. Long-term sequelae are common but not ensured.

Obstetric determinants of neonatal survival: influence of willingness to perform cesarean delivery on survival of extremely low-birth-weight infants. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

OBJECTIVE: Our purpose was to evaluate the relationship between the approach to obstetric management and survival of extremely low-birth-weight infants. STUDY DESIGN: In this prospective observational study we evaluated 713 singleton births of infants weighing < or = 1000 gm during 1 year at the 11 tertiary perinatal care centers of the National Institutes of Child Health and Human Development network of maternal-fetal medicine units. Major anomalies, extramural delivery, antepartum stillbirth, induced abortion, and gestational age < 21 weeks were excluded. The obstetrician's opinion of viability and willingness to perform cesarean delivery in the event of fetal distress were ascertained from the medical record or interview when documentation was unclear. Grade 3 and 4 intraventricular hemorrhage, grade 3 and 4 retinopathy of prematurity, necrotizing enterocolitis requiring surgery, oxygen dependence at discharge or 120 days, and seizures were considered serious morbidity. Survival without serious morbidity was considered intact survival. Logistic regression was used to evaluate the influence of the approach to obstetric management, adjusted for birth weight, growth, gender, presentation, and ethnicity. RESULTS: Willingness to perform cesarean delivery was associated with increased likelihood of both survival (adjusted odds ratio 3.7, 95% confidence interval 2.3 to 6.0) and intact survival (adjusted odds ratio 1.8, 95% confidence interval 1.0 to 3.3). Willingness to intervene for fetal indications appeared to virtually eliminate intrapartum stillbirth and to reduce neonatal mortality. Below 800 gm or 26 weeks, however, willingness to perform cesarean delivery was linked to an increased chance of survival with serious morbidity. Although obstetricians were willing to intervene for fetal indications in most cases by 24 weeks, willingness to perform cesarean delivery was associated with twice the risk for serious morbidity at that gestational age. CONCLUSIONS: The approach to obstetric management significantly influences the outcome of extremely low-birth-weight infants. Above 800 gm or 26 weeks the obstetrician should usually be willing to perform cesarean delivery for fetal indications. Between 22 and 25 weeks willingness to intervene results in greater likelihood of both intact survival and survival with serious morbidity. In these cases patients and physicians should be aware of the impact of the approach to obstetric management and consider the likelihood of serious morbidity and mortality when formulating plans for delivery.

The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network.

OBJECTIVE: To evaluate the presence of fetal fibronectin in the cervix and vagina as a screening test for spontaneous preterm birth. METHODS: Two thousand nine hundred twenty-nine women at ten centers were routinely screened every 2 weeks from 22-24 to 30 weeks for cervical and vaginal fetal fibronectin. A positive test was defined as a value equal to or greater than 50 ng/mL. The relation between a positive test at four gestational ages and spontaneous preterm birth at various intervals after the test was determined. RESULTS: In each testing period, 3-4% of the fetal fibronectin tests were positive. The correlation between cervical and vaginal fetal fibronectin at the same visit was always approximately 0.7 (P < .001), and that between cervical or vaginal fetal fibronectin in consecutive visits was between 0.17 and 0.25 (P < .001). The sensitivity of fetal fibronectin at 22-24 weeks to predict spontaneous preterm birth at less than 28 weeks was 0.63, and the relative risk for a positive versus negative test was 59. The specificity was always 96-98%, whereas the positive predictive value rose from 13% to 36% as the upper limit of the definition of preterm birth was increased from less than 28 to less than 37 weeks. The relative risk for spontaneous preterm birth after a positive fetal fibronectin test compared with a negative fetal fibronectin test varied substantially by testing period and by the definition of spontaneous preterm birth, but always remained greater than 4 and statistically significant. CONCLUSION: A positive cervical or vaginal fetal fibronectin test at 22-24 weeks predicted more than half of the spontaneous preterm births at less than 28 weeks (sensitivity 0.63). As the definition of spontaneous preterm birth was extended to include later gestational ages or when the fetal fibronectin test was performed later in pregnancy, the level of association between a positive fetal fibronectin test and spontaneous preterm birth, while remaining highly significant, tended to decrease. Although fetal fibronectin is an excellent test for predicting spontaneous preterm birth, we present no evidence that the use of this test will result in a reduction in spontaneous preterm birth.

Antimicrobial therapy in expectant management of preterm premature rupture of the membranes.

We review the impact of antimicrobial treatment on maternal and fetal outcome during expectant management of preterm premature rupture of the membranes. Relevant studies were retrieved from Medline (1966 to August, 1994) with the search term fetal-membrane-premature-rupture and antibiotics or antimicrobial, Excerpta Medica (1972 to August, 1994) with the search term premature fetus, membrane rupture, and antibiotic or antimicrobial therapy, and the Cochrane database of systemic reviews with the criterion antibiotics and prelabour rupture of membranes. We also obtained unpublished data from a randomised clinical trial of ceftizoxime versus placebo. The selected studies were randomised controlled trials of systemic antimicrobial therapy for prolongation of gestation in non-labouring women after preterm premature rupture of the membranes. Data extraction was done by a single reviewer. Studies were evaluated for post-randomisation exclusion and other confounding variables that might introduce analytical bias. Analysis was done with SAS statistical software by a blinded investigator. Antimicrobial therapy after preterm premature rupture of the membranes is associated with a reduced number of women delivering within 1 week (62 vs 76%; OR 0.51, 95% CI 0.41-0.68), and reduced diagnosis of maternal morbidity including chorioamnionitis (12 vs 23%; 0.45, 0.33-0.60) and postpartum infection (8 vs 12%; 0.63, 0.41-0.97). Fetal morbidity, including confirmed sepsis (5 vs 9%; 0.57, 0.36-0.88), pneumonia (1 vs 3%; 0.32, 0.11-0.96), and intraventricular haemorrhage (9 vs 14%; 0.65, 0.45-0.92) were less often diagnosed after antimicrobial therapy. Separate analysis of the six placebo-controlled trials revealed similar or improved odds of pregnancy prolongation, chorioamnionitis, neonatal sepsis, postpartum infection, positive infant blood cultures, and pneumonia. Antimicrobial therapy, when used in the expectant management of preterm premature rupture of the membranes is associated with prolongation of pregnancy and a reduction in the diagnosis of maternal and infant morbidity. Further study should be directed towards determination of optimal antimicrobial therapy, increasing pregnancy prolongation, and enhancement of corticosteroid therapy for induction of pulmonary maturity after preterm premature rupture of the membranes.

Risk factors for meconium aspiration syndrome.

OBJECTIVE: To identify potential predictors of meconium aspiration syndrome (MAS) in pregnancies complicated by moderate or thick meconium-stained amniotic fluid (AF). METHODS: In the period 1990-1993, 937 vertex singleton pregnancies with moderate or thick meconium-stained AF were delivered; of these, 39 neonates developed MAS and 898 did not. The two groups were compared retrospectively according to maternal findings, pregnancy outcome, and neonatal complications, using univariate analysis (P < .05 considered significant) and stepwise multiple logistic regression analysis to identify independent significant factors for prediction of MAS and to calculate odds ratios (OR) and 95% confidence intervals. RESULTS: The two groups had a similar mean gestational age at delivery and birth weight. They also had similar incidences of post-dates pregnancies, small and large for gestational age infants, and amnioinfusion use. Univariate analysis identified significant differences between the two groups in 13 variables, two of which were excluded from logistic analysis because of inadequate data. Logistic regression analysis identified only six variables with independent, statistically significant effects on MAS: admission for induction with nonreassuring fetal heart tracing (OR 6.9), need for endotracheal intubation and suctioning below the vocal cords (OR 4.9), 1-minute Apgar score of 4 or less (OR 3.1), present cesarean delivery (OR 3.0), and previous cesarean delivery (OR 2.5). Cigarette smoking was associated with a lower risk for MAS (OR 0.07). The presence of at least one of the five risk factors had a sensitivity of 92%, a specificity of 56%, a positive predictive value of 8%, and a negative predictive value of 99% for MAS. CONCLUSION: Considering the high negative predictive value of the test, infants without any risk factors will not develop MAS and thus can be safely allowed to room with their mothers. Furthermore, this model helps to identify infants who may benefit from 24-hour observation and in counseling women about the neonatal risk for developing MAS.

Erythromycin therapy in preterm premature rupture of the membranes: a prospective, randomized trial of 220 patients.

OBJECTIVES: The use of prophylactic antibiotics in the management of preterm premature rupture of the membranes has not been adequately studied. The purpose of this study was to evaluate the efficacy of oral erythromycin therapy in the prolongation of latency and reduction of infectious morbidity after preterm premature rupture of membranes. STUDY DESIGN: In this randomized, prospective, double-blind, placebo-controlled study, 220 women at 20 to 35 weeks' gestation were evaluated. Subjects received oral erythromycin 333 mg (n = 106) or indistinguishable placebo (n = 114) every 8 hours from randomization to delivery. RESULTS: Prolongation of latency was identified with erythromycin therapy (p = 0.02), particularly for those destined to have chorioamnionitis (p = 0.003) and those with oligohydramnios (p = 0.01). No decrease in the incidence of maternal or neonatal infectious morbidity was seen. CONCLUSIONS: Oral erythromycin delays, but does not prevent, the onset of clinical infection when administered to women with preterm premature rupture of membranes. This regimen does not decrease neonatal morbidity and mortality.

Fetal foot length as a predictor of gestational age.

Ultrasonographic measurement of fetal foot length is useful in the assessment of gestational age. Two hundred twenty-three postpartum and 224 ultrasonographic measurements were performed between 11 and 43 weeks' gestation; 207 postpartum and 160 ultrasonographic measurements met our requirements of secure dates and no physical anomaly or maternal disease. Mean foot length at each week of gestation compared favorably with Streeter's data, based on pathologic specimens, described in 1920. Comparison of curvilinear regression of foot length versus gestational age demonstrated a strong correlation with an R2 value of 0.981; 95% confidence intervals at each week compared favorably with both biparietal diameter and femur length data. Fetal foot length is a reliable parameter for use in the assessment of gestational age and is particularly useful when other parameters do not accurately predict gestational age, for example, hydrocephalus, anencephaly, short limb dysplasia.